ABSTRACT Nipah (NiV) and Hendra (HeV) viruses are highly pathogenic type species of the Henipavirus (HNV) genus within the Paramyxovirinae. Zoonotic transmission of NiV and HeV from their natural fruit bat reservoirs to humans can result in mortality rates in excess of 90%. Originally thought to be limited to Southeast Asia and Australia, the recent discovery of numerous divergent clades of HNVs across Africa, and of Henipa-like viruses (HNLV) in China such as the Mojiang paramyxovirus (MojPV), qualitatively changes the risk- calculus associated with the possible global emergence of these zoonotic viruses. Indeed, we recently found evidence for HNV spillover into human populations at high-risk for zoonotic transmission in Cameroon, which raise urgent questions about potential spillover events that may have remained undetected or misdiagnosed. The recent Ebola epidemic in West Africa underscores the importance of understanding the mechanisms of zoonotic spillover and transmission of highly pathogenic emerging viruses. HNVs use EphrinB2 and EphrinB3, highly conserved cellular proteins, as viral entry receptors. The recent discovery of novel HNVs with differential usage of EphrinB2 and B3 provides new opportunities to study how receptor usage contributes to the pathogenicity and potential for zoonotic spillover of these emergent HNVs. Our overall goal is to elucidate the envelope-receptor interactions of HNVs and HNLVs that contribute to viral tropism, pathogenicity, transmissibility, and the potential for zoonotic spillover. Our primary objective is to understand the structure-function correlates of envelope- receptor interactions in the pathobiology of HNV/HNLV zoonotic infections. A secondary objective is to leverage that understanding to interrogate the rational basis for a vaccine design that might elicit antibodies that are more broadly neutralizing and effective against an ever-expanding spectrum of diverse HNVs. Our driving hypothesis is: the structural plasticity of HNV-Gs accounts for the differential efficiency and choice of receptor usage exhibited by divergent HNVs, and that this contributes to a virulence spectrum among these zoonotic viruses that is equally diverse. To achieve our objectives and interrogate our driving hypothesis, we propose the following Specific Aims: (1) Investigate the role of receptor usage and choice in virus pathogenicity. (2) Evaluate how attachment protein-receptor interactions contribute to transmissibility and the potential for zoonotic spillover. (3) Examine the implications of the structural and phylogenetic diversity of HNVs on vaccine design.